We report a case of cryptococcal meningoencephalitis which challenges the prevailing theory of antigen detection being more sensitive for the diagnosis than CSF biofire.  

60 year old immunocompetent male was admitted with episodes of unsteady gait, staring and picking at his clothes. Examination revealed lethargy and constructional apraxia.  MRI brain showed ventriculomegaly. CSF analysis showed opening pressure 34cm H2O, protein 134, WBC count 62 with 98% lymphocytes. CSF multiplex PCR panel and Cryptococcal antigen were negative. He was started on Topiramate and Acetazolamide.  As he did not improve, repeat lumbar puncture was obtained six days after admission. Repeat CSF PCR panel was positive for cryptococcal DNA, however both serum and CSF cryptococcal antigen were negative.CD4 count was 977 cells/uL. He was started on induction therapy for Cryptococcal meningoencephalitis. A lumbar drain was placed for secondary hydrocephalus. He completed 12 months of maintenance therapy and is doing well on follow up. 

Detection of the capsular antigen by lateral flow assay has widely been believed to be the most reliable diagnostic method for Cryptococcal Meningoencephalitis. The cryptococcal antigen in the specimen diluent binds to gold conjugated anticryptococcal monoclonal antibodies on the test strip, producing a detection line. This test is based on an optimal antigen-antibody ratio,known as the zone of equivalence. A false negative result might be obtained in case of antigen levels greater than 0.14 mg/L (postzone phenomenon), as the excess antigen binds colloidal gold instead of immobilized antibody in the test area of the strip. Hospital laboratories do not routinely test for this occurrence, which can lead to a missed diagnosis.